tbuckley/cabot-search huggingface dataset:
EXTH-35. ANTI-TUMOR AROMATHERAPY FOR MALIGNANT BRAIN TUMORS USING VOLATILE COMPONENTS OF HIBA ESSENTIAL OIL
Authors: Norihiko Saito, Nozomi Hirai, Takuya Nagata, Naoki Kushida, Sho Sato, Yu Hiramoto, Morito Hayashi, Satoshi Iwabuchi
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Glioblastoma is a brain tumor with a very poor prognosis that is highly resistant to treatment. Hiba (Thujopsis dolabrata) has been used as a building material because of its insect repellent effect and refreshing fragrance. In this study, we analyzed the antitumor effects of thujopsen, which is contained in the essential oil of hiba, and investigated its antitumor aroma therapy.Methods and RESULTS We investigated the anti-tumor aroma effect of hiba essential oil on glioblastoma cells (U251, T98G), gastric cancer cells (MKN45), and breast cancer cells (MCF7). The anti-tumor effect of hiba essential oil varied depending on the carcinoma, with strong inhibition of cell proliferation observed in MKN45, U251, and T98G cells. Hinokitiol in hiba essential oil has been reported to have antitumor effects, and we isolated and identified a new antitumor factor, thujopsene, by liquid chromatography analysis. In tumor cell proliferation assays, thujopsen inhibited tumor cell proliferation more rapidly and potently than hinokitiol. Comparing the reach of the two compounds, hinokitiol showed a broader anti-tumor effect than thujopsen. The expression of caspase-3 and caspase-9 was increased by thujopsen, and DARTS analysis identified PKM2 as an intracellular binding protein of thujopsen. DISCUSSION The present study revealed that thujopsen induces apoptosis via caspase-3 and caspase-9. Furthermore, unlike hinokitiol, thujopsen was suggested to exhibit antitumor effects mediated by PKM2. CONCLUSION Thujopsen is a low molecular weight compound and easily evaporates into the air, it is expected to be applied to a new glioblastoma therapy using "aroma".
BIOM-12. PROLONGED RESPONSE TO THIRD-LINE TREATMENT WITH COMBINATION CCNU/TMZ IN AN MGMT METHYLATED IDH-WILDTYPE GLIOBLASTOMA
Authors: Peter Pan, Aya Haggiagi, Fabio Iwamoto
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Multiply recurrent glioblastoma suffers from poor response rates to treatment, and limited durability. We describe a case of an impressive response to third-line CCNU/TMZ. BACKGROUND Headaches brought a 76-year-old man to medical attention. MRI identified an enhancing right temporal mass -- path following resection demonstrated glioblastoma (IDH-wildtype, MGMT-methylated, TERT mutant; PTEN Y68H, CDKN2A/B loss, CCND3 amplification; VUS in POLE, ATM, GRIN2A, and ROS1). He received hypofractionated RT 40.05Gy/15-fractions plus 21-days concurrent TMZ 75 mg/m2, then 5-day-on / 23-day-off TMZ (150 mg/m2 cycles #1-3; 200 mg/m2 subsequent). MRI pre-cycle #6, nearly 6 months post-RT, showed increased enhancement/FLAIR consistent with local progression (POD).Second-Line: After screen-fail for clinical trial, initiated off-label regorafenib 160 mg/d, 21-days-on/7-days-off -- with partial response in enhancement at 3 weeks. With dose-reduction to 120 mg/d cycles #2-3 (for mounting fatigue), enhancement progressively worsened. Despite resuming higher 160 mg/d for cycle #4, enhancement progressed, consistent with POD.Third-Line: Given presence of MGMT promoter methylation (and extrapolating from CeTeG/NOA-09), combination CCNU 100 mg/m2 (day 1) and TMZ 100 mg/m2 (days 2-6; 8-week cycle) was started. There was improvement in enhancement/FLAIR, which continued to improve gradually through 6 cycles of CCNU/TMZ. Durability of response was surprising -- MRIs stable/improved at 15 months since starting CCNU/TMZ. DISCUSSION This case illustrates impressive response to CCNU/TMZ in the third-line. Delayed RT treatment effect is less likely given time elapsed from RT at initial progression (after 5 cycles of adjuvant TMZ), convincing but short-lived improvement to regorafenib (that progressively worsened through 3 more regorafenib cycles), and robust response only with CCNU/TMZ. He was also never on steroids (except post-operatively) nor bevacizumab. This suggests that improvement was mediated by antitumor effect against progressing tumor, rather than delayed RT treatment effect. MGMT methylation may have played a role in this patient's response to dual alkylator therapy.
ANGI-05. VASCULAR NORMALIZATION IN MURINE GLIOBLASTOMA IS CONTROLLED BY APLN-SIGNALING AND CAN BE MONITORED BY DCE-MR IMAGING IN VIVO
Authors: Roland Kälin, Enio Barci, Huabin Zhang, Geoffrey Topping, Jiying Cheng, Sandra Sühnel, Joerg-Christian Tonn, Franz Schilling, Rainer Glass
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE Glioblastoma (GBM) expansion is accompanied by aberrant tumor vascularization. We demonstrated that the peptide hormone Apelin (APLN) controls GBM neo-vascularization and that the APLN-receptor antagonist Apelin-F13A improved the efficiency and reduced the invasive side effect of established antiangiogenic therapy. Here we investigated if Apelin-F13A blunts the formation of vasogenic edema, which can be monitored by MRI in vivo. METHODS To investigate the role of APLN -signaling in regulating the tightness of the tumor vasculature we performed in vivo leakage assays using Evans-Blue dye and fluorescent dextran. By confocal immunofluorescence, we characterized the maturation of the tumor vasculature with respect to pericyte-coverage and established a dynamic contrast enhanced (DCE) MR imaging protocol to follow vascular edema formation. RESULTS We found that Evans-Blue extravasation is significantly increased by 3-fold in APLNKO tumors compared to controls. Uptake of fluorescent Dextran by CD31+ endothelia was quantified and increased massively from 200μm2 per high magnification field (HMF) in wildtype to 3500μm2 per HMF in APLNKO tumors. Interestingly, intracerebral infusion of Apelin-F13A enhanced pericyte coverage of the tumor vasculature by 50%, decreased Evans-Blue extravasation from 25 μg/ml in controls to 8 μg/ml in treated tumors significantly and efficiently reversed the APLN-dependent vasogenic edema assessed by comparison of T2w-MRI to HE tumor volumes. To follow vasogenic edema formation in vivo, T1w 3D FLASH images were acquired every second over a 360s time course after gadolinium-based MR-contrast agent injection and demonstrated a delayed washout of the contrast in APLN-deficient GBM. CONCLUSION Together, our study shows that DCE-MRI can document APLN-dependent intratumoral vascular normalization and allows inspecting vasogenic edema formation in vivo. In addition to its anti-angiogenic / anti-invasive effect, Apelin-F13A can potently reduce vasogenic edema and might thus serve as a multimodal therapy for the treatment of human GBM in the future.
TMIC-15. AGE-RELATED MARKERS FOR SENESCENCE INCREASE IN THE OLDER ADULT EXTRATUMORAL MOUSE BRAIN DUE TO GLIOBLASTOMA
Authors: April Bell, Margaret Johnson, Erik Ladomersky, Miri Kim, Junfei Zhao, Jason Miska, Lijie Zhai, Kristen Lauing, Evridiki Asimakidou, Prashant Bommi, James Chandler, Xinlei Mi, Masha Kocherginski, Rimas Lukas, Derek Wainwright
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE The median age of onset for glioblastoma (GBM; IDHwt) is 68-70 years. Age is a strong prognostic factor for GBM patient outcomes such that overall survival in older adults is less than their younger counterparts – even after adjustment for MGMT promoter methylation status. Aging is associated with increased levels of senescence in the brain. Several age-related neurological disorders have been shown to improve with senolytic treatments. Here, we explored the effects and therapeutic neutralization of syngeneic brain tumors on increasing senescence levels in the extratumoral brain (ie. outside of the brain tumor) of young and old mice. METHODS General RNA-sequencing, as well as single-cell (sc) RNA-sequencing was performed on extratumoral tissue from young (8-12 weeks) and older adult (80-90 weeks) C57BL/6 mice with or without GL261 and key markers were validated with RT-PCR. The combined effects of the senolytics, dasatinib and quercetin, with radiation, anti-PD-1 mAb, and IDO enzyme inhibitor treatment, was also investigated. RESULTS General- and sc-RNA sequencing revealed a distinct gene expression profile in the extratumoral brain of older mice with syngeneic GL261 as compared to all other groups. RT-PCR results confirmed that the brain tumor increased gene expression for senescence levels, p53, and NFkB signaling in the older adult extratumoral brain. Expression of the senescence marker p16INK4A was primarily localized to oligodendrocyte progenitor cells in the older adult brain. The combinatorial treatment of senolytics with RT, anti-PD-1 mAb, and IDO enzyme inhibitor led to a synergistic survival benefit in older adult mice with GL261 as compared to the treatment with senolytics, or immunotherapy, alone. CONCLUSIONS The data suggest that the extratumoral brain may be responsible in-part for the poorer outcomes of older adults with GBM and that treatment approaches that target senescent cells may provide clinical benefit.
NIMG-37. JOINT LEARNING OF IMAGING AND GENOMIC DATA REVEALS DISTINCT GLIOBLASTOMA SUBTYPES
Authors: Jun Guo, Anahita Fathi Kazerooni, Hamed Akbari, Erik Toorens, Chiharu Sako, Elizabeth Mamourian, Constantinos Koumenis, Stephen Bagley, Zev A Binder, Robert Lustig, Donald O'Rourke, Tapan Ganguly, Spyridon Bakas, MacLean Nasrallah, Christos Davatzikos
Journal: Neuro-Oncology (2022)

Abstract PURPOSE The significant heterogeneity of glioblastoma is typically displayed on both phenotypical and molecular levels. Non-invasive in vivo approaches to characterize this heterogeneity would potentially facilitate personalized therapies. Here we leverage advanced unsupervised machine learning to integrate radiomic imaging features and genomics to identify distinct subtypes of glioblastoma. METHODS A retrospective cohort of 571 IDH-wildtype glioblastoma patients were collected with pre-operative multi-parametric MRI (T1, T1CE, T2, T2-FLAIR, DSC, DTI) scans (available in 462/571 patients) and targeted next-generation sequencing (NGS) data (available in 355/571 patients). Radiomic features (n= 971) were extracted from these MRI scans and a subset of 12 features were selected by L21-norm minimization. A total of 14 key driver genes in the 5 main pathways that are most frequently altered in glioblastoma were chosen. Subtypes were identified by a joint learning approach called Anchor-based Partial Multi-modal Clustering (APMC) on both radiomic and genomic modalities. RESULTS Three distinct glioblastoma subtypes were discovered by APMC based on 14-dimension NGS data together with 12 selected radiomic features representing characteristics from histograms, shape, and volumetric measures for different tumor sub-regions. The identified subtypes were 1) high-risk; 2) medium-risk; and 3) low-risk, in terms of their overall survival outcome in Kaplan-Meier analysis (p= 5.52e-6, log-rank test; HR= 1.51, 95%CI:1.20-1.74, Cox proportional hazard model). The three subtypes also displayed different molecular characteristics: subtype 1 exhibited increased frequency of mutation in [EGFR, PIK3CA, PTEN, NF1], subtype 3 showed frequently mutated [PDGFRA, ATRX], while subtype 2 did not show significant differences for mutations in any of these genes. CONCLUSION Our results revealed the synergistic value of integrated radiomic signatures and molecular characteristics for glioblastoma subtyping. Joint learning on both modalities could help better understand the molecular basis of phenotypical signatures of glioblastoma and further provide insights into the biologic underpinnings of tumor formation and progression.
CTNI-36. INITIATION OF A PHASE 1 DOSE-ESCALATING STUDY OF WEEKLY DIRECT-TO-BRAIN ADMINISTRATION OF SOLUBILISED FORMULATION OF PANOBINOSTAT (MTX110) IN PATIENTS WITH RECURRENT GLIOBLASTOMA (MAGIC-G1 STUDY)
Authors: Annick Desjardins, Kelly Conlon, Hannah Gunning, Rhian Davies, Jordan Komisarow, Robert Cavaliere, Dmitry Zamoryakhin
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Glioblastoma (GBM) is the most aggressive primary brain tumour in adults, leading to universal recurrence despite aggressive surgical and chemotherapeutic treatment. Post-recurrence, median overall survival is 6 to 10 months and treatment options are very limited. One of the biggest challenges in treating GBM is achieving high local drug concentration; systemic administration of cytotoxic agents has failed in the past due to this limitation. Convection enhanced delivery (CED) is a ‘direct-to-brain’ drug delivery method that previously demonstrated its usefulness in overcoming this challenge. MTX110 (Midatech Pharma Ltd) is a water-soluble form of panobinostat, that demonstrated cytotoxic activity in 4 GBM cell lines (U87MG, U251MG, U118MG and T98G) with an average IC50 value around 40nM which also translated into pre clinical in vivo efficacy, in combination with radiotherapy1. Delivery of MTX110 via an implanted pump and CED catheter system in patients with GBM appears to be an attractive treatment option, that allows for therapeutic doses of the drug to be delivered weekly directly to the tumour, thus avoiding systemic administration and therefore toxicity. This has previously been demonstrated in investigator-initiated studies of paediatric patients with diffuse intrinsic pontine glioma. METHOD MAGIC-G1 study is a Phase 1 two-cohort dose-escalating study that will assess safety and feasibility of intermittent intratumoral administration of MTX110 by CED to rGBM patients; either as a single agent (Cohort 1) or in combination with lomustine (Cohort 2). Eligible patients will have a catheter system and an abdominal refillable pump implanted in an aseptic manner, with the tip of the catheter positioned stereotactically at the centre of the tumour. 48-hour infusions will be administered weekly until disease progression and doses of 30, 60 and 90 mM will be investigated. Cohort 1 recruitment will be completed before Cohort 2 starts dosing. Study results are expected in 2023.
QOL-18. CAN QUALITY OF LIFE FOR BRAIN TUMOR SURVIVORSHIP CARE
Authors: Abigail Koehler, Yehudit Rothman, Diego Gomez Enriquez, Michelle Kirschner, Melissa Erickson, Meera Rastogi, Claudia Rebola, Soma Sengupta
Journal: Neuro-Oncology (2022)

Abstract Cancer survivorship is an important area of medicine as it focuses on the quality of life of patients after experiencing cancer and cancer treatment. Thankfully, many patients survive cancers and other benign tumor diagnoses but must live with the side effects and subsequent consequences of their treatment. These, sometimes lifelong, effects can diminish quality of life and interfere with day-to-day activities. A number of therapy tools have been developed to aid in survivorship care, but how can we advance new digital therapy tools for cancer survivorship and brain-related diseases, specifically quality of life? The University of Cincinnati has curated an innovative team of faculty and students across disciplines to develop digital applications to emphasize cancer and brain tumor survivorship and create new methods for health and wellbeing at the hands of people. This includes the CAN Quality of Life applications which use novel technologies to administer digital pre-existing therapies. The first, ARMCan, is a digital music therapy instrument used by breast cancer patients with post-chemotherapy brain fog. The second, ARTCan, is a digital art therapy platform in which vestibular schwannoma and NF2 patients with mood issues can complete self-guided art activities. ARTCan is partnered with ARCCan, animal robotic-like companions. A narrative application for cancer survivors and caregivers is being developed. These CAN applications hope to improve the quality of life for the people they serve by improving executive function and mood, respectfully. ARMCan and ARTCan/ARCCan pilot feasibility studies are currently accruing subjects at our institution.
MODL-11. NOVEL IMMUNOTHERAPY MODEL IN AGGRESSIVE PEDIATRIC H3K27M MUTANT GLIOMAS WITH INDUCIBLE TGFBR2 AND LAG3 EXPRESSION
Authors: Vladimir Ljubimov, Paul Linesch, Sara Sabet, Viktoria Krutikova, Shaunt Mehdikhani, David Rincon Fernandez Pacheco, Moise Danielpour, Joshua Breunig
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Gliomas are considered immunologically “cold” tumors that mask themselves from the immune system. Immunotherapy, a breakthrough for cancer treatment, remains inefficient for gliomas. H3K27M mutant diffuse midline glioma has poor survival. Using our innovative mosaic analysis with dual recombinases technology (Cell 2019), we further created a novel murine model of H3K27M glioma with an inducible expression of LAG3 and TGFBR2 to make the tumor recognizable by the immune system. This allows studying molecular mechanisms of “perfect” immunotherapy in pediatric gliomas with histone H3.3 mutations. METHODS To make a novel murine model, H3K27M plasmids with doxycycline-inducible expression for TGFBR2 and LAG3 were designed, sequenced, and replicated. For in vitro validation, murine neuronal stem cells were nucleofected with these plasmids, grown and sorted. Doxycycline was added to the experimental group in vitro to induce expression. The plasmids were then electroporated into neonatal MGMT mice (n=21) of both genders. Control mice were used on a standard diet (n=9) and experimental mice (n=12) were given doxycycline in food to induce TGFBR2 and LAG3 expression in vivo. Mice were followed up for survival. RESULTS Plasmid sequencing validation demonstrated their high purity. In vitro nucleofected neuronal stem cells showed significant increase in TGFBR2 and LAG3 expression by immunofluorescent staining after addition of doxycycline. The mouse survival study showed a significant benefit with treatment group surviving 46% longer (135 ± 41.9 days vs. 92.6 ± 32.7 days in the control group, p=0.030). Conclusion and Future Directions: We have successfully modified H3K27M glioma to have inducible expression of TGFBR2 and LAG3 to simulate “perfect” immunotherapy. The survival study showed a significant survival benefit. The development of organoid transplants for more uniform testing and next-generation sequencing is ongoing. This can lead to the emergence of novel immune therapies and uncover novel mechanisms of tumor response to treatment.
INNV-13. INDOLENT H3 K27-ALTERED DIFFUSE MIDLINE GLIOMA
Authors: Sudarshawn Damodharan, Jeffrey Helgager, Diane Puccetti
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION H3 K27-altered diffuse midline glioma (DMG) is an aggressive central nervous system tumor that is universally fatal with a median survival of 8-12 months after diagnosis. Here we present a patient who was incidentally found to have a lesion within the right thalamus on brain magnetic resonance imaging (MRI). Twelve years later, she was found to have a brain mass within the same area with pathology consistent with an H3 K27-altered DMG. Case Description: A 14-year-old female presented with new onset left sided numbness and weakness, blurry vision and a right sided temporal headache. Her past medical history is significant for severe persistent asthma and anoxic brain injury secondary to a cardiopulmonary arrest at 2-years-of-age due to an asthma exacerbation. She has had multiple MRIs of her brain since her initial insult which initially showed the presence of a T2/FLAIR hyperintense lesion within the right medial thalamus in addition to chronic central nervous system changes. The right thalamic lesion was stable in size between images obtained at 2-years and 4-years of age. Her current physical exam is significant for decreased strength to her left upper and lower extremities. Brain MRI with and without contrast is obtained, demonstrating partial effacement of the third ventricle due to mass effect from an enlarging mass from the right thalamus. Biopsy of the lesion demonstrated an H3 K27-altered DMG, WHO grade 4. Our patient went on to receive palliative radiation therapy with 59.4 Gy over 33 fractions. DISCUSSION This case illustrates an unusual presentation of an H3 K27-altered DMG with an indolent course, diagnosed twelve years after the initial MRI finding. This proposes the possibility of multiple factors playing a role in the oncogenesis of these aggressive tumors and that further research is warranted.
RADT-31. 68GA-DOTATATE PET VERSUS MRI-BASED TREATMENT PLANNING FOR POST-OPERATIVE AND INTACT MENINGIOMA: A DOSIMETRIC ANALYSIS
Authors: Haley Perlow, Rahul Prasad, Michael Siedow, Yevgeniya Gokun, Joseph McElroy, Jennifer Matsui, Catherine Cadieux, Daniel Eiler, Sean Odou, Mark Addington, Jana Ivanidze, Joseph Bovi, Christopher Kleefisch, Wesley Zoller, Joshua Palmer
Journal: Neuro-Oncology (2022)

Abstract Background Nearly all meningiomas express somatostatin receptor 1/2 (SSTR1/SSTR2); therefore, SSTR ligands such as 68Ga-DOTATATE can be utilized for meningioma radiotherapy treatment planning. Incorporation of 68Ga-DOTATATE PET assists with target delineation and may reduce the dose to organs-at-risk (OARs). We hypothesize that 68Ga-DOTATATE PET-based treatment plans will reduce dose to OARs when compared to MRI-based plans. METHODS All treatment plans were rendered on computed tomography (CT) planning datasets, using RapidArc and 6MV photon energy. Two arcs were positioned on the coplanar axis with alternated collimator settings of 0 and 90 degrees to promote MLC sparing with a third unique vertex arc chosen independently to spare normal brain tissue and associated organs at risk (OAR). For MRI structures, a 1 cm expansion from the gross tumor volume (GTV) created a clinical treatment volume (CTV)60. A 2 cm expansion created a CTV54. For PET structures, a 1 cm expansion from the GTV created a CTV60. A 3 mm isotropic expansion created planning treatment volumes (PTVs). Plans were optimized such that Dmax to brainstem remained limited to 60Gy or less and Dmax to optic structures was limited to 54Gy or less. RESULTS 18 meningioma patients were included (9 post-operative, 9 intact). The mean PTV volume using MRI was 258 ccs (306 ccs for post-operative, 210 ccs for intact), and the mean PTV volume using PET was 60 ccs (97 ccs for post-operative, 91 ccs for intact). The mean radiation dose to both optic nerves, the optic chiasm, both hippocampi, and the brainstem was reduced favoring PET-based treatment plans for both post-operative and intact patients. CONCLUSION Our study shows that incorporation of 68Ga-DOTATATE PET can reduce dose to OARs for post-operative and intact patients, and this difference may translate to reduced toxicity. 68Ga-DOTATATE PET guided radiation treatments are worthy of future prospective investigation.